fig3

Figure 3. Potential approaches for HER3-targeted cancer therapy. Nrdp1 and NEDD4 are E3 ubiquitin ligases of HER3, which promote the ubiquitination of HER3 and 26S proteasome degradation, and subsequently downregulate the protein level of HER3. The activated AR acts as a transcription factor facilitating Nrdp1 transcription. Moreover, AKT inhibits the deubiquitinating enzyme USP8, while USP8 downregulates Nrdp1 levels. In addition, AKT inhibits the expression of FoXO transcription factor, and FoXO family transcription factors FoXO1 and FoXO3a can target the HER3 promoter to promote HER3 transcription. FoXD3 and AP-2γ are also transcriptional activators of HER3, while MYC is a transcriptional suppressor of HER3. Epigenetic inhibitors entinostat inhibits HDAC, HDAC can activate miR-125a, miR-125b, and miR-205; these three miRNAs can complement with 3’UTR of HER3 mRNA, subsequently downregulate HER3 levels. Furthermore, miR-450b-3p can also control HER3 levels. HER: Human epidermal growth factor receptor; NEDD4: neural precursor cell expressed developmentally down-regulated 4; Nrdp1: neuregulin receptor degradation protein 1; Ub: ubiquitin; ATP: adenosine triphosphate; ADP: adenosine diphosphate; NRG: neuregulin; AR: androgen receptor; USP8: ubiquitin-specific protease 8; PI3K: phosphatidylinositide 3-kinases; AKT: also named PKB (protein kinase B); FoXO: forkhead box O; HDAC: histone deacetylase; AP-2γ: activator protein-2γ; MYC: myelocytomatosis; 3’UTR: 3’-untranslated region.